rs148298842

Positions:

• chr2-108753853-A-C
• chr2-108753853-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BP6 BS2

The NM_006267.5(RANBP2):​c.2084A>C​(p.Glu695Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000767 in 1,611,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00056 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00079 (0 hom.)
• Consequence: RANBP2 NM_006267.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 5.26

Genes affected

RANBP2 (HGNC:9848): (RAN binding protein 2) RAN is a small GTP-binding protein of the RAS superfamily that is associated with the nuclear membrane and is thought to control a variety of cellular functions through its interactions with other proteins. This gene encodes a very large RAN-binding protein that immunolocalizes to the nuclear pore complex. The protein is a giant scaffold and mosaic cyclophilin-related nucleoporin implicated in the Ran-GTPase cycle. The encoded protein directly interacts with the E2 enzyme UBC9 and strongly enhances SUMO1 transfer from UBC9 to the SUMO1 target SP100. These findings place sumoylation at the cytoplasmic filaments of the nuclear pore complex and suggest that, for some substrates, modification and nuclear import are linked events. This gene is partially duplicated in a gene cluster that lies in a hot spot for recombination on chromosome 2q. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RANBP2. . Gene score misZ -0.77637 (greater than the threshold 3.09). Trascript score misZ 3.8106 (greater than threshold 3.09). GenCC has associacion of gene with Leigh syndrome, familial acute necrotizing encephalopathy.
• BP4: Computational evidence support a benign effect (MetaRNN=0.07865384).
• BP6: Variant 2-108753853-A-C is Benign according to our data. Variant chr2-108753853-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 469435.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}. Variant chr2-108753853-A-C is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 85 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RANBP2	NM_006267.5	c.2084A>C	p.Glu695Ala	missense_variant	15/29	ENST00000283195.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RANBP2	ENST00000283195.11	c.2084A>C	p.Glu695Ala	missense_variant	15/29	1	NM_006267.5	P1
RANBP2	ENST00000697737.1	c.2084A>C	p.Glu695Ala	missense_variant	15/27
RANBP2	ENST00000697740.1	c.2006A>C	p.Glu669Ala	missense_variant	15/27

Frequencies

GnomAD3 genomes AF: 0.000558 AC: 85 AN: 152236 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00104

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000284 AC: 71 AN: 250132 Hom.: 0 AF XY: 0.000280 AC XY: 38 AN XY: 135496

Gnomad AFR exome AF: 0.000318

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000460

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000789 AC: 1151 AN: 1459612 Hom.: 0 Cov.: 34 AF XY: 0.000755 AC XY: 548 AN XY: 726108

Gnomad4 AFR exome AF: 0.000210

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.000279

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.000959

Gnomad4 OTH exome AF: 0.000615

GnomAD4 genome AF: 0.000558 AC: 85 AN: 152236 Hom.: 0 Cov.: 31 AF XY: 0.000551 AC XY: 41 AN XY: 74378

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00104

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000753 Hom.: 0

Bravo AF: 0.000495

ExAC AF: 0.000404 AC: 49

EpiCase AF: 0.00120

EpiControl AF: 0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 18, 2021

The c.2084A>C (p.E695A) alteration is located in exon 15 (coding exon 15) of the RANBP2 gene. This alteration results from a A to C substitution at nucleotide position 2084, causing the glutamic acid (E) at amino acid position 695 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Familial acute necrotizing encephalopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 19, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.51
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.71	D
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.021
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.079	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.086
Sift	Benign	0.24	T
Sift4G	Uncertain	0.021	D
Polyphen		0.43	B
Vest4		0.25
MVP		0.36
MPC		1.1
ClinPred		0.032	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.083
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs148298842; hg19: chr2-109370309; COSMIC: COSV51701771; COSMIC: COSV51701771;